Preparation and use of ortho-sulfonamido heteroaryl hydroxamic acids as matrix metalloproteinase and tace inhibitors

ABSTRACT

The present invention relates to the discovery of novel, low molecular weight, non-peptide inhibitors of matrix metalloproteinases (e.g. gelatinases, stromelysins and collagenases) and TNF-α converting enzyme (TACE, tumor necrosis factor-α converting enzyme) which are useful for the treatment of diseases in which these enzymes are implicated such as arthritis, tumor growth and metastasis, angiogenesis, tissue ulceration, abnormal wound healing, periodontal disease, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, graft rejection, cachexia, anorexia, inflammation, fever, insulin resistance, septic shock, congestive heart failure, inflammatory disease of the central nervous system, inflammatory bowel disease, HIV infection, age related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren&#39;s syndrome, myopia, ocular tumors, ocular angiogenesis/neovascularization. 
     The TACE and MMP inhibiting ortho-sulfonamido aryl hydroxamic acids of the present invention are represented by the formula ##STR1## where the hydroxamic acid moiety and the sulfonamido moiety are bonded to adjacent carbons on group A where A is defined as: 
     a 5-6 membered heteroaryl having from 1 to 3 heteroatoms independently selected from N, O, and S and optionally substituted by R 1 , R 2  and R 3  ; 
     and Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8  and R 9  are described in the specification, 
     and the pharmaceutically acceptable salts thereof and the optical isomers and diastereomers thereof.

This application claims the benefit of prior U.S. ProvisionalApplication No. 60/028,969 filed Oct. 16, 1996

BACKGROUND OF THE INVENTION

The present invention relates to the discovery of novel, low molecularweight, non-peptide inhibitors of matrix metalloproteinases (e.g.gelatinases, stromelysins and collagenases) and TNF-α converting enzyme(TACE, tumor necrosis factor-α converting enzyme) which are useful forthe treatment of diseases in which these enzymes are implicated such asarthritis, tumor metastasis, tissue ulceration, abnormal wound healing,periodontal disease, bone disease, proteinuria, aneurysmal aorticdisease, degenerative cartilage loss following traumatic joint injury,demyelinating diseases of the nervous system and HIV infection.

Matrix metalloproteinases (MMPs) are a group of enzymes that have beenimplicated in the pathological destruction of connective tissue andbasement membranes Woessner, J. F., Jr. FASEB J. 1991, 5, 2145;Birkedal-Hansen, H.; Moore, W. G. I.; Bodden, M. K.; Windsor, L. J.;Birkedal-Hansen, B.; DeCarlo, A.; Engler, J. A. Crit. Rev. Oral Biol.Med. 1993, 4, 197; Cawston, T. E. Pharmacol. Ther. 1996, 70, 163;Powell, W. C.; Matrisian, L. M. Cur. Top. Microbiol. and Immunol. 1996,213, 1!. These zinc containing endopeptidases consist of several subsetsof enzymes including collagenases, stromelysins and gelatinases. Ofthese classes, the gelatinases have been shown to be the MMPs mostintimately involved with the growth and spread of tumors, while thecollagenases have been associated with the pathogenesis ofosteoarthritis Howell, D. S.; Pelletier, J.-P. In Arthritis and AlliedConditions; McCarthy, D. J.; Koopman, W. J., Eds.; Lea and Febiger:Philadelphia, 1993; 12th Edition Vol. 2, pp. 1723; Dean, D. D. Sem.Arthritis Rheum. 1991, 20, 2; Crawford, H. C; Matrisian, L. M. InvasionMetast. 1994-95, 14, 234; Ray, J. M.; Stetler-Stevenson, W. G. Exp.Opin. Invest. Drugs, 1996, 5, 323!.

It is known that the level of expression of gelatinase is elevated inmalignancies, and that gelatinase can degrade the basement membranewhich may lead to tumor metastasis Powell, W. C.; Matrisian, L. M. Cur.Top. Microbiol. and Immunol. 1996, 213, 1; Crawford, H. C; Matrisian, L.M. Invasion Metast. 1994-95, 14, 234; Ray, J. M.; Stetler-Stevenson, W.G. Exp. Opin. Invest. Drugs, 1996, 5, 323; Himelstein, B. P.;Canete-Soler, R.; Bernhard, E. J.; Dilks, D. W.; Muschel, R. J. InvasionMetast. 1994-95, 14, 246; Nuovo, G. J.; MacConnell, P. B.; Simsir, A.;Valea, F.; French, D. L. Cancer Res. 1995, 55, 267-275; Walther, M. M.;Levy, A.; Hurley, K.; Venzon, D.; Linehen, W. M.; Stetler-Stevenson, W.J. Urol. 1995, 153 (Suppl. 4), 403A; Tokuraku, M; Sato, H.; Murakami,S.; Okada, Y.; Watanabe, Y.; Seiki, M. Int. J. Cancer, 1995, 64, 355;Himelstein, B.; Hua, J.; Bernhard, E.; Muschel, R. J. Proc. Am. Assoc.Cancer Res. Ann. Meet. 1996, 37, 632; Ueda, Y.; Imai, K.; Tsuchiya, H.;Fujimoto, N.; Nakanishi, I.; Katsuda, S.; Seiki, M.; Okada, Y. Am. J.Pathol. 1996, 148, 611; Gress, T. M.; Mueller-Pillasch, F.; Lerch, M.M.; Friess, H.; Buechler, M.; Adler, G. Int. J. Cancer, 1995, 62, 407;Kawashima, A.; Nakanishi, I.; Tsuchiya, H.; Roessner, A.; Obata, K.;Okada, Y. Virchows Arch., 1994, 424, 547-552.!. Angiogenesis, requiredfor the growth of solid tumors, has also recently been shown to have agelatinase component to its pathology Crawford, H. C; Matrisian, L. M.Invasion Metast. 1994-95, 14, 234; Ray, J. M.; Stetler-Stevenson, W. G.Exp. Opin. Invest. Drugs, 1996, 5, 323.!. Furthermore, there is evidenceto suggest that gelatinase is involved in plaque rupture associated withatherosclerosis Dollery, C. M.; McEwan, J. R.; Henney, A. M. Circ. Res.1995, 77, 863; Zempo, N.; Koyama, N.; Kenagy, R. D.; Lea, H. J.; Clowes,A. W. Arterioscler. Thromb. Vasc. Biol. 1996, 16, 28; Lee, R. T.;Schoen, F. J.; Loree, H. M.; Lark, M. W., Libby, P. Arterioscler.Thromb. Vasc. Biol. 1996, 16, 1070.!. Other conditions mediated by MMPsare restenosis, MMP-mediated osteopenias, inflammatory diseases of thecentral nervous system, skin aging, tumor growth, osteoarthritis,rheumatoid arthritis, septic arthritis, corneal ulceration, abnormalwound healing, bone disease, proteinuria, aneurysmal aortic disease,degenerative cartilage loss following traumatic joint injury,demyelinating diseases of the nervous system, cirrhosis of the liver,glomerular disease of the kidney, premature rupture of fetal membranes,inflammatory bowel disease, periodontal disease, age related maculardegeneration, diabetic retinopathy, proliferative vitreoretinopathy,retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren'ssyndrome, myopia, ocular tumors, ocular angiogenesis/neovascularizationand corneal graft rejection.

The hypothesis that MMPs are important mediators of the tissuedestruction that occurs in arthritis has long been considered, since itwas first recognized that these enzymes are capable of degradingcollagens and proteoglycans which are the major structural components ofcartilage Sapolsky, A. I.; Keiser, H.; Howell, D. S.; Woessner, J. F.,Jr.; J. Clin. Invest. 1976, 58, 1030; Pelletier, J.-P.;Martel-Pelletier, J.; Howell, D. S.; Ghandur-Mnaymneh, L.; Enis, J. E.;Woessner, J. F., Jr., Arthritis Rheum. 1983, 26, 63.!, and continues todevelop as new MMPs are identified. For example, collagenase-3 (MMP-13)was cloned from breast cancer cells in 1994, and the first report thatit could be involved in arthritis appeared in 1995 Freiji, J. M.;Diez-Itza, I.; Balbin, M.; Sanchez, L. M.; Blasco, R.; Tolivia, J.;Lopez-Otin, C. J. Biol. Chem. 1994, 269, 16766; Flannery, C. R.; Sandy,J. D. 102-17, 41st Ann. Meet. Orth. Res. Soc. Orlando, Fla. Feb. 13-16,1995.!. Evidence is accumulating that implicates MMP-13 in thepathogenesis of arthritis. A major structural component of articularcartilage, type II collagen, is the preferred substrate for MMP-13 andthis enzyme is significantly more efficient at cleaving type II collagenthan the other collagenases Knauper, V.; Lopez-Otin, C.; Smith, B.;Knight, G.; Murphy, G. J. Biol. Chem., 1996, 271, 1544-1550; Mitchell,P. G.; Magna, H. A.; Reeves, L. M.; Lopresti-Morrow, L. L.; Yocum, S.A.; Rosner, P. J.; Geoghegan, K. F.; Hambor, J. E. J. Clin. Invest.1996, 97, 761.!. MMP-13 is produced by chondrocytes, and elevated levelsof MMP-13 has been found in human osteoarthritic tissues Reboul, P.;Pelletier, J-P.; Hambor, J.; Magna, H.; Tardif, G.; Cloutier, J-M.;Martel-Pelletier, J. Arthritis Rheum. 1995, 38 (Suppl. 9), S268;Shlopov, B. V.; Mainardi, C. L.; Hasty, K. A. Arthritis Rheum. 1995, 38(Suppl. 9), S313; Reboul, P.; Pelletier, J-P.; Tardif, G.; Cloutier,J-M.; Martel-Pelletier, J. J. Clin. Invest. 1996, 97, 2011!. Potentinhibitors of MMPs were described over 10 years ago, but the poorbioavailability of these early peptidic, substrate mimetic MMPinhibitors precluded their evaluation in animal models of arthritis.More bioavailable, non-peptidic MMP inhibitors may be preferred for thetreatment of diseases mediated by MMPs.

TNF-α converting enzyme catalyzes the formation of TNF-α from membranebound TNF-α precursor protein. TNF-α is a pro-inflammatory cytokine thatis now thought to have a role in rheumatoid arthritis, septic shock,graft rejection, insulin resistance and HIV infection in addition to itswell documented antitumor properties. For example, research withanti-TNF-α antibodies and transgenic animals has demonstrated thatblocking the formation of TNF-α inhibits the progression of arthritisRankin, E. C.; Choy, E. H.; Kassimos, D.; Kingsley, G. H.; Sopwith, A.M.; Isenberg, D. A.; Panayi, G. S. Br. J. Rheumatol. 1995, 34, 334;Pharmaprojects, 1996, Therapeutic Updates 17 (Oct.), au197-M2Z.!. Thisobservation has recently been extended to humans as well. Otherconditions mediated by TNF-α are congestive heart failure, cachexia,anorexia, inflammation, fever, inflammatory disease of the centralnervous system, and inflammatory bowel disease.

It is expected that small molecule inhibitors of gelatinase and TACEtherefore have the potential for treating a variety of disease states.While a variety of MMP and TACE inhibitors have been identified anddisclosed in the literature, the vast majority of these molecules arepeptidic or peptide-like compounds that may have bioavailability andpharmacokinetic problems that would limit their clinical effectiveness.Low molecular weight, potent, long-acting, orally bioavailableinhibitors of gelatinases, collagenases and/or TACE are therefore highlydesirable for the potential chronic treatment of the above mentioneddisease states. Several non-peptide, sulfur-containing hydroxamic acidshave recently been disclosed and are listed below.

U.S. Pat. Nos. 5,455,258, 5,506,242 and 5,552,419, as well as Europeanpatent application EP606,046A1 and WIPO international publicationsWO96/00214 and WO97/22587 disclose non-peptide matrix metalloproteinaseinhibitors of which the compound CGS27023A is representative. Thediscovery of this type of MMP inhibitor is further detailed byMacPherson, et. al. in J. Med. Chem., (1997), 40, 2525. Additionalpublications disclosing sulfonamide based MMP inhibitors which arevariants of the sulfonamide-hydroxamate shown below, or the analogoussulfonamide-carboxylates, are European patent application EP-757984-A1and WIPO international publications WO95/35275, WO95/35276, WO96/27583,WO97/19068 and WO97/27174. ##STR2##

Publications disclosing β-sulfonamide-hydroxamate MMP inhibitor analogsof CGS 27023A in which the carbon alpha to the hydroxamic acid has beenjoined in a ring to the sulfonamide nitrogen, as shown below, includeWIPO international publications WO96/33172 and WO97/20824. ##STR3##

The German patent application DE19,542,189-A1 discloses additionalexamples of cylic sulfonamides as MMP inhibitors. In this case thesulfonamide-containing ring is fused to a phenyl ring to form anisoquinoline. ##STR4##

Analogs of the sulfonamide-hydroxamate MMP inhibitors in which thesulfonamide nitrogen has been replaced by a carbon atom, as shown in thegeneral structure below, are European patent application EP-780386-A1and WIPO international publication WO97/24117. ##STR5##

SUMMARY OF THE INVENTION

The TACE and MMP inhibiting ortho-sulfonamido heteroaryl hydroxamicacids of the present invention are represented by the formula ##STR6##where the hydroxamic acid moiety and the sulfonamido moiety are bondedto adjacent carbons of group A where:

A is a 5-6 membered heteroaryl optionally substituted by R¹, R² and R³ ;having from 1 to 3 heteroatoms independently selected from N, O, and S;

Z is aryl or heteroaryl, or heteroaryl fused to a phenyl,

where aryl is phenyl, naphthyl, or phenyl fused to a heteroaryl ,wherein heteroaryl is as defined above, and wherein aryl and heteroarylmay be optionally substituted by R¹, R², R³ and R⁴ ;

where heteroaryl is as defined above and optionally substituted by R¹,R², R³ and R⁴ ;

R¹, R², R³ and R⁴ are independently defined as --H, --COR⁵, --F, --Br,--Cl, --I, --C(O)NR⁵ OR⁶, --CN, --OR⁵, --C₁ -C₄ -perfluoroalkyl,--S(O)_(x) R⁵ where x is 0-2, --OPO(OR⁵)OR⁶, --PO(OR⁶)R⁵, --OC(O)NR⁵ R⁶,--COOR⁵, --CONR⁵ R⁶, --SO₃ H, --NR⁵ R⁶, --NR⁵ COR⁶, --NR⁵ COOR⁶, --SO₂NR⁵ R⁶, --NO₂, --N(R⁵)SO₂ R⁶, --NR⁵ CONR⁵ R⁶, --NR⁵ C(═NR⁶)NR⁵ R⁶,3-6-membered cycloheteroalkyl having one to three heteroatomsindependently selected from N, O, and S, optionally having 1 or 2 doublebonds and optionally substituted by one to three groups each selectedindependently from R⁵, -aryl or heteroaryl as defined above, SO₂ NHCOR⁵or --CONHSO₂ R⁵ where R⁵ is not H, -tetrazol-5-yl, --SO₂ NHCN, --SO₂NHCONR⁵ R⁶ or straight chain or branched --C₁ -C₆ alkyl, --C₃ -C₆-cycloalkyl optionally having 1 or 2 double bonds, --C₂ -C₆ -alkenyl, or--C₂ -C₆ -alkynyl each optionally substituted with --COR⁵, --CN, --C₂-C₆ alkenyl, --C₂ -C₆ alkynyl, --OR⁵, --C₁ -C₄ -perfluoroalkyl,--S(O)_(x) R⁵ where x is 0-2, --OC(O)NR⁵ R⁶, --COOR⁵, --CONR⁵ R⁶, --SO₃H, --NR⁵ R⁶, --NR⁵ COR⁶, --NR⁵ COOR⁶, --SO₂ NR⁵ R⁶, --NO₂, --N(R⁵)SO₂R⁶, --NR⁵ CONR⁵ R⁶, --C₃ -C₆ cycloalkyl as defined above, --C₃ -C₆cycloheteroalkyl as defined above, -aryl or heteroaryl as defined above,--SO₂ NHCOR⁵ or --CONHSO₂ R⁵ where R⁵ is not hydrogen, --OPO(OR⁵)OR⁶,--PO(OR⁶)R⁵, -tetrazol-5-yl, --C(O)NR⁵ OR⁶, --NR⁵ C(═NR⁶)NR⁵ R⁶, --SO₂NHCONR⁵ R⁶ or --SO₂ NHCN;

with the proviso that when R¹ and R² are on adjacent carbons of A, R¹and R² together with the carbons to which they are attached can form a5-7 membered saturated or unsaturated carbocyclic ring or heterocyclicring containing one to two heteroatoms selected independently from N, O,and S, each optionally substituted with one to four groups selectedindependently from R⁴ ;

R⁵ and R⁶ are independently defined as H, aryl and heteroaryl as definedabove, --C₃ -C₆ -cycloalkyl as defined above, --C₃ -C₆ -cycloheteroalkylas defined above, --C₁ -C₄ -perfluoroalkyl, or straight chain orbranched --C₁ -C₆ alkyl, --C₂ -C₆ -alkenyl, or --C₂ -C₆ -alkynyl eachoptionally substituted with --OH, --COR⁸, --CN, --C(O)NR⁸ OR⁹, --C₂ -C₆-alkenyl, --C₂ -C₆ -alkynyl, --OR⁸, --C₁ -C₄ -perfluoroalkyl, --S(O)_(x)R⁸ where x is 0-2, --OPO(OR⁸)OR⁹, --PO(OR⁸)R⁹, --OC(O)NR⁸ R⁹, --COOR⁸,--CONR⁸ R⁹, --SO₃ H, --NR⁸ R⁹, --NCOR⁸ R⁹, --NR⁸ COOR⁹, --SO₂ NR⁸ R⁹,--NO₂, --N(R⁸)SO₂ R⁹, --NR⁸ CONR⁸ R⁹, --C₃ -C₆ cycloalkyl as definedabove, --C₃ -C₆ -cycloheteroalkyl as defined above, -aryl or heteroarylas defined above, --SO₂ NHCOR⁸ or --CONHSO₂ R⁸ where R⁸ is not hydrogen,-tetrazol-5-yl, --NR⁸ C(═NR⁹)NR⁸ R⁹, --SO₂ NHCONR⁸ R⁹, --SO₂ NHCN;

R⁷ is hydrogen, straight chain or branched --C₁ -C₆ -alkyl, --C₂ -C₆-alkenyl, or --C₂ -C₆ -alkynyl each optionally substituted with --OH,--COR⁵, --CN, --C₂ -C₆ -alkenyl, --C₂ -C₆ -alkynyl, --OR⁵, --C₁ -C₄-perfluoroalkyl, --S(O)_(x) R⁵ where x is 0-2, --OPO(OR⁵)OR⁶,--PO(OR⁵)R⁶, --OC(O)NR⁵ R⁶, --COOR⁵, --CONR⁵ R⁶, --SO₃ H, --NR⁵ R⁶,--NR⁵ COR⁶, --NR⁵ COOR⁶, --SO₂ NR⁵ R⁶, --NO₂, --N(R⁵)SO₂ R⁶, --NR⁵ CONR⁵R⁶, --C₃ -C₆ cycloalkyl as defined above, --C₃ -C₆ -cycloheteroalkyl asdefined above, -aryl or heteroaryl as defined above, --SO₂ NHCOR⁵ or--CONHSO₂ R⁵ where R⁵ is not hydrogen, -tetrazol-5-yl, --NR⁵ C(═NR6)NR⁵R⁶, --C(O)N R⁵ OR⁶, --SO₂ NHCONR⁵ R⁶ or --SO₂ NHCN;

or R⁷ is phenyl or naphthyl, optionally substituted by R¹, R², R³ and R⁴or a 5 to 6 membered heteroaryl group having 1 to 3 heteroatoms selectedindependently from N, O, and S and optionally substituted by R¹, R², R³and R⁴ ;

or R⁷ is C₃ -C₆ cycloalkyl or 3-6 membered cycloheteroalkyl as definedabove;

or R⁷ --CH₂ --N-A-, where A is as defined above, can form a non-aromatic1,2-heteroaryl-fused 7-10 membered heterocyclic ring optionallycontaining an additional heteroatom selected from O, S and N whereinsaid heterocyclic ring may be optionally fused to another benzene ring;

R⁸ and R⁹ are independently H, aryl or heteroaryl as defined above, --C₃-C₇ -cycloalkyl or cycloheteroalkyl as defined above, --C₁ -C₄-perfluoroalkyl, straight chain or branched --C₁ -C₆ -alkyl, --C₂ -C₆-alkenyl, or --C₂ -C₆ -alkynyl, each optionally substituted withhydroxy, alkoxy, aryloxy, --C₁ -C₄ -perfluoroalkyl, amino, mono- anddi-C₁ -C₆ -alkylamino, carboxylic acid, carboalkoxy and carboaryloxy,nitro, cyano, carboxamido primary, mono- and di-C₁ -C₆ -alkylcarbamoyl;

and the pharmaceutically acceptable salts thereof and the opticalisomers and diastereomers thereof.

Preferred compounds are those wherein both of the carbons of A adjacentto the carbon bearing the sulfonamido group have a substituent otherthan hydrogen. Also preferred are compounds where Z is 4-alkoxyphenyl,4-aryloxyphenyl or 4-heteroaryloxyphenyl.

The term "heteoaryl" as defined hereinabove includes, but is not limitedto, pyrrole, furan, thiophene, pyridine, pyrimidine, pyridazine,pyrazine, triazole, pyrazole, imidazole, isothiazole, thiazole,isoxazole and oxazole. The term "5 to 7 membered saturated orunsaturated heterocyclic ring" includes, but is not limited tooxazolidine, thiazolidine, imidazolidine, tetrahydrofuran,tetrahydrothiophene, tetramethylene sulfone, dihydropyran,tetrahydropyran, piperidine, pyrrolidine, dioxane, morpholine, azepineand diazepine. The term "heteroaryl fused to a phenyl" includes, but isnot limited to, indole, isoindole, benzofuran, benzothiophene,benzoisothiazole, quinoline, isoquinoline, quinoxaline, quinazoline,benzotriazole, indazole, benzimidazole, benzothiazole, benzisoxazole,and benzoxazole.

The following compounds (I-V) which may be used in preparing compoundsof the invention are known and references are given hereinbelow. Thislist is included for illustrative purposes only and is not to beconstrued as limiting in any way. ##STR7## Literature references forthese materials are as follows:

Compound I:

a) Dolle, R E; Hoyer, D W; Schmidt, S J; Ross, T M; Rinker, J M; Ator, MA Eur. Pat. Appl. EP-628550

b) Wermuth, C-G; Schlewer, G; Bourguignon, J-J; Maghioros, G; Bouchet,M-J et. al. J. Med. Chem (1989), 32, 528-537

c) Yutugi, S et. al. Chem. Pharm. Bull, (1971) 19, 2354-2364

d) Dolle, R E; Hoyer, D; Rinker, J M; Ross, T M; Schmidt, S J Biorg.Med. Chem. Lett (1977) 7, 1003-1006

Compound II: Camparini, A; Ponticelli, F; Tedeschi, P. J. Chem. Soc.,Perkin Trans.1 (1982), 10, 2391-4.

Compound III: Muller, C. E.; Geis, U.; Grahner, B.; Lanzner, W.; Eger,K. J. Med. Chem. (1996), 39, 2482.

Compound IV: Muller, C. E.; Geis, U.; Grahner, B.; Lanzner, W.; Eger, K.J. Med. Chem. (1996), 39, 2482.

Compound V: Commercially available.

The compounds of this invention are shown to inhibit the enzymes MMP-1,MMP-9, MMP-13 and TNF-α converting enzyme (TACE) and are thereforeuseful in the treatment of arhritis, tumor metastasis, tissueulceration, abnormal wound healing, periodontal disease, graftrejection, insulin resistance, bone disease and HIV infection.

DETAILED DESCRIPTION OF THE INVENTION

The following reaction scheme (Scheme I) depicts the general method ofsynthesis of the invention compounds from an ortho amino heteroarylcarboxylic acid ester. For purposes of illustration only, the orthoamino heteroaryl carboxylic acid ester shown is3-amino-thiophene-4-carboxylic acid methyl ester, wherein A isthiophene, which is sulfonylated with p-methoxybenzenesulfonyl chloride,wherein Z is 4-methoxyphenyl, and then alkylated with benzyl bromide,wherein R⁷ is benzyl. The resulting ester is subsequently converted intothe corresponding hydroxamic acid in 2 steps. Obviously, otherheteroaromatic groups having an amino group adjacent to a carboxy groupand having optional substituents R¹, R² and R³ where Z and R⁷ are asdefined hereinabove can be used in the general reaction scheme toprepare invention hydroxamic acids. ##STR8##

Shown in Scheme II is the synthesis of an example of the inventionwherein A is pyridyl. The ortho-amino ester is constucted via metalationand subsequent carboxylation of the BOC-protected amino-pyridine.Deprotection of the resulting ester compound, (2), followed bysulfonylation of the amine, (3), provides (4) wherein Z is4-methoxyphenyl. Alkylation of the NH-sulfonamide of (4) as in Scheme I,followed by hydrolysis of the ester functionality and conversion of theresulting carboxylic acid, (6), into the corresponding hydroxamic acidresults in the desired pyridyl-hydroxamate, (7). Additionalpyridyl-hydroxamates are available through the same route. ##STR9##

Schemes III and IV illustrate two methods for incorporating amino groupsinto the substituent attached to the sulfonamide nitrogen of thecompounds of the invention. Thus, in Scheme III the NH-sulfonamide isalkylated with propargyl bromide to provide the propargyl sulfonamide.This alkyne is reacted with paraformaldehyde in the presence of aprimary or secondary amine and cuprous chloride to give the propargylamine which is converted, as before, to the desired hydroxamic acid.##STR10##

In Scheme IV, selective hydrolysis of the ester of thep-carboethoxybenzyl sulfonamide group provides a mono-carboxylic acid.This acid may be converted into an amide (not shown), followed byconversion of the second ester, A-CO₂ R, into the correspondinghydroxamate, or reduced to the corresponding alcohol with diborane. Thealcohol may be converted into the analogous amine via the benzylicbromide, followed by conversion of the the ester, A-CO₂ R, into thecorresponding hydroxamate. ##STR11##

Methods for synthesizing variations of substituents on the sulfonyl arylgroup are shown in Schemes V through VIII. As shown in Scheme V, biarylsulfonyl groups are synthesized by Suzuki couplings on abromo-substituted benzene sulfonamide. The starting bromo-substitutedbenzene sulfonamide is synthesized from the commercially availablebromobenzenesulfonyl chloride and the amino-acid or amino-ester, H₂N-A-CO₂ R, followed by alkylation of the resulting NH-sulfonamide.Alternatively, the bromo aryl sulfonamide is converted into thecorresponding boronic acid by the method of Ishiyama, et.al. J. Org.Chem. (1995), 60, 7508! followed by coupling with an appropriate arylhalide. ##STR12##

Methods for synthesizing sulfonyl aryl ethers are shown in Schemes VIthrough VIII. In Scheme VI biaryl ethers, or aryl heteroaryl ethers, aresynthesized starting from the known sulfonyl chlorides (see for example:Zook S E; Dagnino, R; Deason, M E, Bender, S L; Melnick, M J WO97/20824). ##STR13##

Alternatively, the biaryl ethers may be prepared from the correspondingboronic acids or via the sulfonyl phenols as shown in Scheme VII.##STR14##

Aryl ethers may also be prepared via displacement of the fluorine from apara-fluorobenzene sulfonamide, as shown in Scheme VIII. Aryl or alkylethers may be prepared in this manner. ##STR15##

Basic salts of the hydroxamic acids can be formed with pharmaceuticallyacceptable alkali-forming metal cations such as lithium, sodium,potassium, calcium and aluminum. Acid addition salts can be formed whena substitutent contains a basic amino group using a pharmaceuticallyacceptable inorganic or organic acid such as hydrochloric, hydrobromic,phosphoric, sulfuric, acetic, benzoic, succinic, lactic, malic, maleic,fumaric or methanesulfonic acids.

The following specific examples are included for illustrative purposesand are not to be construed as limiting to this disclosure in any way.Other procedures useful for the preparation of compounds of thisinvention may be apparent to those skilled in the art of organicsynthesis.

EXAMPLE 1 3-(4-Methoxy-benzenesulfonylamino)-thiophene-2-carboxylic acidmethyl ester

To a solution of 5.00 g (0.032 mol) of 3-amino-2-carbomethoxythiophenedissolved in 40 mL of chloroform was added 7.73 mL (0.032 mol) ofpyridine followed by 6.57 g (0.032 mol) of p-methoxybenzenesulfonylchloride. The reaction mixture was stirred at room temperature for 5 hand then washed with 3N HCl and water. The organics were then dried overNa₂ SO₄, filtered and concentrated in vacuo. The resulting cream coloredsolid was washed with ether and dried in vacuo to provide 6.89 g (66%)of the desired sulfonamide. Electrospray Mass Spec 328.2 (M+H).

EXAMPLE 2 4-(4-Methoxy-benzenesulfonylamino)-thiophene-3-carboxylic acidmethyl ester

In the same manner as described in Example 1, 5.00 g (0.026 mol) of3-amino-4-carbomethoxythiophene hydrochloride provided 3.50 g (41%) ofthe desired sulfonamide as a brown solid after trituration with ether.Electrospray Mass Spec 328.2 (M+H).

EXAMPLE 35-(4-Methoxy-benzenesulfonylamino)-1-methyl-1H-pyrazole-4-carboxylicacid ethyl ester

In the same manner as described in Example 1, 2.00 g (0.012 mol) of1-methyl-2-amino-3-carboethoxy-pyrazole provided 0.923 g (23%) of thedesired sulfonamide as a white solid after recrystallization fromEtOAc/Hexanes. Electrospray Mass Spec 340.2 (M+H).

EXAMPLE 43-(4-Methoxy-benzenesulfonylamino)-4-methyl-thiophene-2-carboxylic acidmethyl ester

In the same manner as described in Example 1, 4.14 g (0.024 mol) of3-amino-4-methyl-2-carbomethoxy thiophene provided 4.89 g (47%) of thedesired sulfonamide as a white solid after trituration with ether. EIMass Spec 340.9 (M⁺).

EXAMPLE 5 3-Benzyl-(4-methoxy-benzenesulfonyl)-amino!-thiophene-2-carboxylic acidmethyl ester

To a solution of 2.0 g (6.116 mmol) of the product of Example 1 in 25 mLof DMF was added 0.257 g (6.422 mmol) of 60% sodium hydride. Theresulting mixture was stirred for 30 min at room temperature and then0.76 mL (6.422 mmol) of benzyl bromide was added. This reaction mixturewas stirred overnight at room temperature, poured into water and thenextracted with ether. The combined organics were washed with water andbrine, dried over MgSO₄, filtered and concentrated in vacuo. The residuewas chromatographed on silica gel eluting with EtOAc/Hexanes (1:3) toprovide 1.62 g (65%) of the desired product as white crystals. CI MassSpec: 418 (M+H).

EXAMPLE 6 4-Benzyl-(4-methoxy-benzenesulfonyl)-amino!-thiophene-3-carboxylic acidmethyl ester

In the same manner as described in Example 5, 1.50 g (4.587 mmol) of theproduct of Example 2 provided 1.257 g (66%) of the desired product as abrown oil after chromatography on silica gel eluting with EtOAc/Hexanes(1:10). CI Mass Spec: 418 (M+H).

EXAMPLE 7 5-Benzyl-(4-methoxy-benzenesulfonyl)-amino!-1-methyl-1H-pyrazole-4-carboxylicacid ethyl ester

In the same manner as described in Example 5, 0.843 g (2.484 mmol) ofthe product of Example 3 provided 0.924 g (87%) of the desired productas a white solid after trituration with ether. CI Mass Spec: 430 (M+H).

EXAMPLE 8 3-Benzyl-(4-methoxy-benzenesulfonyl)-amino!-4-methyl-thiophene-2-carboxylicacid methyl ester

In the same manner as described in Example 5, 2.00 g (4.64 mmol) of theproduct of Example 4 provided 1.648 g (68%) of the desired product as awhite solid after tituration with ether. CI Mass Spec: 432 (M+H).

EXAMPLE 9 3-Benzyl-(4-methoxy-benzenesulfonyl)-amino!-thiophene-2-carboxylic acid

To a mixture of 1.494 g (3.583 mmol) of the product of Example 5dissolved in 15 mL of methanol and 15 mL of THF was added 15 mL of 1NNaOH solution. The reaction mixture was stirred at room temperature for36 h and the organics were removed in vacuo. The resulting mixture wasacidified with 10% HCl and extracted with EtOAc. The combined organicswere washed with water and brine, dried over MgSO₄, filtered andconcentrated in vacuo. The resulting residue was triturated with etherand filtered to provide 1.327 g (92%) of the desired carboxylic acid asa white solid. CI Mass Spec: 404 (M+H).

EXAMPLE 10 4-Benzyl-(4-methoxy-benzenesulfonyl)-amino!-thiophene-3-carboxylic acid

In the same manner as described in Example 9, 1.157 g (2.775 mmol) ofthe product of Example 6 provided 0.94 g (84%) of the desired carboxylicacid as a tan solid after trituration with ether. Electrospray MassSpec: 404 (M+H).

EXAMPLE 11 5-Benzyl-(4-methoxy-benzenesulfonyl)-amino!-1-methyl-1H-pyrazole-4-carboxylicacid

To a solution of 0.799 g (1.862 mmol) of the product of Example 7 in 20mL of methanol/THF (1:1) was added 9.3 mL of 1N sodium hydroxidesolution and the resulting mixture was heated to reflux for 18 h. Thereaction was then cooled to room temperature and the organics wereremoved in vacuo. The resulting mixture was acidified with 10% HCl andextracted with EtOAc. The combined organics were washed with water andbrine, dried over MgSO₄, filtered and concentrated in vacuo. Theresulting residue was triturated with ether and filtered to provide0.697 g (93%) of the desired carboxylic acid as a white solid.Electrospray Mass Spec: 402 (M+H).

EXAMPLE 12 3-Benzyl-(4-methoxy-benzenesulfonyl)-amino!-4-methyl-thiophene-2-carboxylicacid

In the same manner as described in Example 11, 1.366 g (2.622 mmol) ofthe product of Example 8 provided 1.16 g (87%) of the desired carboxylicacid as a white solid after trituration with ether. Electrospray MassSpec: 416 (M-H)-.

EXAMPLE 13 3-Benzyl-(4-methoxy-benzenesulfonyl)-amino!-thiophene-2-carboxylic acidhydroxyamide

To a solution of 0.80 g (1.985 mmol) of the product of Example 9 in 20mL of dichloromethane was added 0.154 mL of DMF followed by 2.0 mL of2.0M oxalyl chloride and the resulting reaction mixture was stirred atroom temperature for 1 h.

In a separate flask, 1.66 mL (11.91 mmol) of triethylamine was added toa 0° C. mixture of 0.552 g (7.94 mmol) of hydroxylamine hydrochloride in8.7 mL of THF and 2.2 mL of water. After this mixture had stirred for 15min at 0 degrees, the acid chloride solution was added to it in oneportion and the resulting solution was allowed to warm to roomtemperature with stirring overnight. The reaction mixture was thenacidified to pH3 with 10% HCl and extracted with EtOAc. The combinedorganic layers were dried over Na₂ SO₄, filtered and concentrated invacuo. The crude residue was triturated with ether to provide 0.66 g(80%) of the desired hydroxamic acid as a white solid. Electrospray MassSpec: 419 (M+H).

EXAMPLE 14 4-Benzyl-(4-methoxy-benzenesulfonyl)-amino!-thiophene-3-carboxylic acidhydroxyamide

In the same manner as described in Example 13, 0.80 g (1.985 mmol) ofthe product of Example 10 gave 0.61 g (73%) of the desired hydroxamicacid as a white solid. Electrospray Mass Spec: 419 (M+H).

EXAMPLE 15 5-Benzyl-(4-methoxy-benzenesulfonyl)-amino!-1-methyl-1H-pyrazole-4-carboxylicacid hydroxyamide

In the same manner as described in Example 13, 0.580 g (1.446 mmol) ofthe product of Example 11 gave 0.446 g (74%) of the desired hydroxamicacid as a white solid. Electrospray Mass Spec: 417 (M+H).

EXAMPLE 16 3-Benzyl-(4-methoxy-benzenesulfonyl)-amino!-4-methyl-thiophene-2-carboxylicacid hydroxyamide

In the same manner as described in Example 13, 0.50 g (0.986 mmol) ofthe product of Example 12 gave 0.30 g (58%) of the desired hydroxamicacid as a white solid. CI Mass Spec: 433 (M+H).

EXAMPLE 175-Bromo-4-(4-methoxy-benzenesulfonylamino)-thiophene-3-carboxylic acidmethyl ester

To a solution of the product of Example 2 in 5.0 mL of AcOH--CHCl₃ (1:1)at room temperature was added 0.299 g (1.682 mmol) of N-bromosuccimide.The reaction was stirred for 18 h and then diluted with ether, washedwith water and saturated sodium bicarbonate solution, dried over MgSO₄,filtered and concentrated in vacuo. The tan solid residue was washedwith ether-hexanes (1:1) to provide 0.504 g (81%) of the desired productas a tan solid. Electrospray Mass Spec: 406.1 (M+H)+

EXAMPLE 18 4-Benzyl-(4-methoxy-benzenesulfonyl)-amino!-5-bromo-thiophene-3-carboxylicacid methyl ester

In the same manner as described in Example 5, 0.424 g (1.044 mmol) ofthe product of Example 17 gave 0.400 g (77%) of the desired hydroxamicacid as a white solid. Electrospray Mass Spec: 496.1 (M+H)+

EXAMPLE 19 4-Benzyl-(4-methoxy-benzenesulfonyl)-amino!-5-bromo-thiophene-3-carboxylicacid

In the same manner as described in Example 11, 0.356 g (0.718 mmol) ofthe product of Example 18 gave 0.290 g (84%) of the desired hydroxamicacid as a white solid. Electrospray Mass Spec: 482.1 (M+H)+

EXAMPLE 20 4-Benzyl-(4-methoxy-benzenesulfonyl)-amino!-5-bromo-thiophene-3-carboxylicacid hydroxyamide

In the same manner as described in Example 13, 0.250 g (0.519 mmol) ofthe product of Example 19 gave 0.222 g (86%) of the desired hydroxamicacid as a white solid. Electrospray Mass Spec: 497.1 (M+H)+

EXAMPLE 21 4-Benzyl-(4-methoxy-benzenesulfonyl)-amino!-5-ethynyl-thiophene-3-carboxylicacid methyl ester

To a solution of 0.294 g (0.634 mmol) of the product of Example 18 in2.5 mL of DMF and 2.5 mL of triethylamine was added 0.448 mL (3.168mmol) of timethylsilylacetylene, 0.022 g (0.032 mmol) ofbis(triphenylphosphine)-palladium(II)dichloride and 3 mg ofcopper(I)iodide. The reaction mixture was then heated to 80° C. for 6 hand then cooled to room temperature and diluted with ether. The organicswere washed with 5% HCl solution, water and brine, dried over MgSO₄,filtered and concentrated in vacuo. The residue was dissolved in 5 mL ofTHF, 1 mL of 1M tetrabutylammonium flouride-THF solution was added andthe reaction was stirred at room temperature for 1 h, then diluted withether, washed with 5% HCl solution, water and brine, dried over MgSO₄,filtered and concentrated in vacuo. The residue was chromatographed onsilica eluting with EtOAc-Hex (1:5) to provide 0.159 g (61%) of thedesired product as a brown oil. Electrospray Mass Spec: 442.2 (M+H)⁺

EXAMPLE 22 4-Benzyl-(4-methoxy-benzenesulfonyl)-amino!-5-ethynyl-thiophene-3-carboxylicacid

In the same manner as described in Example 11, 0.136 g (0.333 mmol) ofthe product of Example 21 provided 0.075 g (57%) of the desired productas a tan solid after chromatography on silica eluting with EtOAc-Hexanes(1:1). Electrospray Mass Spec: 428.1 (M+H)+

EXAMPLE 23 4-Benzyl-(4-methoxy-benzenesulfonyl)-amino!-5-ethynyl-thiophene-3-carboxylicacid hydroxyamide

In the same manner as described in Example 13, 0.055 g (0.634 mmol) ofthe product of Example 22 provided 0.044 g (77%) of the desired productas a brown foam. Electrospray Mass Spec: 443.1 (M+H)+.

EXAMPLE 24 5-Bromo-4-(4-methoxybenzenesulfonyl)-pyridin-3-ylmethylamino!thiophene-3-carboxylicacid methyl ester

To a solution of 4.80 g (11.82 mmol) of the product of Example 17dissolved in 5.0 mL of DMF was added 2.04 g (12.41 mmol) of 3-picolylchloride hydrochloride and 4.89 g (35.46 mmol) of potassium carbonate.The reaction mixture was then stirred at room temperature for 18 h,diluted with water and extracted with ether. The oragnics were thenextracted with 6N HCl solution and the aqueous acid layer was thenbasified with 6N NaOH solution and then extracted with ether. Theresulting ether layer was dried over sodium sulfate, filtered andconcentrated in vacuo to provide 4.16 g (71%) of the desired product asa tan solid. Electrospray Mass Spec: 498 (M+H).

EXAMPLE 25 5-Bromo-4-(4-methoxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino!thiophene-3-carboxylicacid

To a solution of 0.40 g (0.860 mmol) of the product of Example 24 in 9.0mL of THF-MeOH (1:1) was added 0.072 g (1.72 mmol) of lithium hydroxidemonohydrate. The reaction mix was heated to reflux for 18 h and thenconcentrated in vacuo. The residue was was washed with THF and filtered.The filtrate was concentrated in vacuo to provide 0.388 g (100%) of thedesired product as a white foam. Electrospray Mass Spec: 483 (M+H).

EXAMPLE 26 5-Bromo-4-(4-methoxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino!thiophene-3-carboxylicacid hydroxyamide

To a solution of 0.82 mL (1.63 mmol) of a 2M solution of oxalyl chloridein CH₂ Cl₂ at 0° C. was added 0.126 mL (1.63 mmol) of DMF and themixture was stirred at 0° C. for 15 min, then let warm to roomtemperature and stirred for an additional 1 h. A solution of 0.374 g(0.817 mmol) of the product of Example 193, in 1 mL of DMF, was thenadded to the reaction mixture and the reaction was stirred for 1 h atroom temperature.

In a separate flask, 1.70 mL (12.25 mmol) of triethylamine was added toa 0° C. mixture of 0.567 g (8.165 mmol) of hydroxylamine hydrochloridein 8.1 mL of THF and 2.3 mL of water. After this mixture had stirred for15 min at 0° C., the acid chloride solution was added to it in oneportion and the resulting solution was allowed to warm to roomtemperature with stirring overnight. The reaction mixture next wasdiluted with CH₂ Cl₂ and washed with water and saturated sodiumbicarbonate solution. The organic layer was dried over Na₂ SO₄, filteredand concentrated in vacuo. The crude residue was triturated with etherto provide 0.235 g (61%) of the desired hydroxamic acid as a tan foam.Electrospray Mass Spec: 498 (M+H).

EXAMPLE 27 tert-Butyl N-(2,6-dimethoxy-3-pyridyl)carbamate

To a suspension of 3-amino-2,6-dimethoxypyridine (1.5 g, 7.87 mmol) wasadded di-tert-butyl dicarbonate (3.43 g, 15.7 mmol). The solution washeated at reflux for 36 hours, cooled to room temperature, and dilutedwith H₂ O. The aqueous solution was extracted 3 times with EtOAc, theorganic extracts were combined, washed with brine, dried over MgSO₄,concentrated in vacuo. The residue was purified by column chromatographyusing hexane/ethyl acetate as eluant (gradient 100% to 4/1) to provide2.00 g (100%) of tert-butyl N-(2,6-dimethoxy-3-pyridyl)carbamate ayellow oil. Electrospray Mass Spec: 254.9 (M+H)+

EXAMPLE 28 tert-ButylN-(4-carbomethoxy-2,6-dimethoxy-3-pyridyl)carbamate

The product of Example 27 (1 g, 3.93 mmol) was dissolved in Et₂ O (35mL) and TMEDA (1.7 mL, 1.18 mmol) and cooled to -78° C. n-Butyllithium(4.75 mL, 11.87 mmol) was added dropwise and the reaction was allowed tostir for 15 minutes at -78° C. before warming to -10° C. for 2.5 hours.The solution was cooled back to -78° C. and methyl chloroformate (0.6mL, 7.8 mmol) dissolved in Et₂ O (4.5 mL) was added dropwise. Thereaction was held at -78° C. for 10 minutes and then warmed to -10° C.and allowed to stir for 1.5 hours before quenching with NH₄ Cl (sat).The reaction mixture was extracted 3× with EtOAc. The organics werecombined, washed with brine, dried over MgSO₄, concentrated in vacuo.The residue was purified by column chromatography using hexane/ethylacetate as eluant (gradient 9/1 to 4/1) to provide 0.423 g (34%) oftert-butyl N-(4-carbomethoxy-2,6dimethoxy-3-pyridyl)carbamate as a whitesolid. Electrospray Mass Spec: 312.8 (M+H)+

EXAMPLE 29 Methyl 3-amino-2,6-dimethoxyisonicotinate

p-Toluene sulfonic acid hydrate (0.282 g, 1.48 mmol) was dissolved intoluene (11 mL) and heated to reflux overnight with azeotropic removalof H₂ O (Dean-Stark trap). The next day, the reaction was cooled to roomtemperature and the product of Example 28, dissolved in toluene (4 mL),was added. The reaction was heated back to reflux for 0.5 hours. Thereaction was cooled to room temperature and poured into NaHCO₃ (sat) andextracted 3 times with ether. The organics were combined, washed withbrine, dried over MgSO₄, concentrated in vacuo. The residue was purifiedby column chromatography using hexane/ethyl acetate as eluant (gradient100% to 9/1) to provide 0.278 g (97%) of methyl3-amino-2,6-dimethoxyisonicotinate as a yellow solid. Electrospray MassSpec: 212.8 (M+H)+

EXAMPLE 30 Methyl3-(4-methoxy-benzenesulfonylamino)-2,6-dimethoxy-isonicotinate

To a solution of the product of Example 29 (0.278 g, 1.31 mmol) inpyridine (2 mL) was added p-methoxybenzenesulfonyl chloride (0.28 g,1.38 mmol). The reaction mixture was stirred at room temperatureovernight and was then quenched with H₂ O. The mixture was extracted 3times with ether. The organics were combined, washed with brine, driedover MgSO₄, concentrated in vacuo to provide 0.444 g (89%) of methyl3-(4-methoxy-benzenesulfonylamino)-2,6-dimethoxy-isonicotinate as asolid. Electrospray Mass Spec: 382.8 (M+H)+

EXAMPLE 31 Methyl 3-Benzyl-(4-methoxy-benzenesulfonyl)-amino!-2,6-dimethoxy-isonicotinate

The product of Example 30 (0.444 g, 1.16 mmol) was dissolved in DMF (4mL) and cooled to 0° C. Benzyl bromide (0.186 mL, 1.6 mmol) followed byNaH (56 mg, 1.39 mmol, 60% dispersion in mineral oil) were added and thereaction was allowed to warm to room temperature. After 1 h, thereaction was diluted with water and extracted 4× Et₂ O. The organicswere combined, washed with brine, dried over MgSO₄, concentrated invacuo to provide 0.545 g (100%) of pure methyl 3-Benzyl-(4-methoxy-benzenesulfonyl)-amino!-2,6-dimethoxy-isonicotinate asan oil. Electrospray Mass Spec: 472.9 (M+H)+

EXAMPLE 32 3-Benzyl-(4-methoxy-benzenesulfonyl)-amino!-2,6-dimethoxy-isonicotinicacid

The product of Example 31 was hydrolyzed to the corresponding carboxylicacid using the procedure of Example 25 to provide 3-Benzyl-(4-methoxy-benzenesulfonyl)-amino!-2,6-dimethoxy-isonicotinicacid. Electrospray Mass Spec: 459.0 (M+H)+

EXAMPLE 33 3-Benzyl-(4-methoxy-benzenesulfonyl)-amino!-N-hydroxy-2,6-dimethoxy-isonicotinamide

The carboxylic acid product of Example 32 was converted to thecorresponding hydroxamic acid, 3-Benzyl-(4-methoxy-benzenesulfonyl)-amino!-N-hydroxy-2,6-dimethoxy-isonicotinamideusing the procedure of Example 26. Electrospray Mass Spec: 474.0 (M+H)+

PHARMACOLOGY Procedures for Measuring MMP-1, MMP-9, and MMP-13Inhibition

These assays are based on the cleavage of a thiopeptide substrates suchas Ac-Pro-Leu-Gly(2mercapto-4 methyl-pentanoyl)-Leu-Gly-OEt by thematrix metalloproteinases MMP-1, MMP-13 (collagenases) or MMP-9(gelatinase), which results in the release of a substrate product thatreacts colorimetrically with DTNB (5,5'-dithiobis(2-nitro-benzoicacid)). The enzyme activity is measured by the rate of the colorincrease. The thiopeptide substrate is made up fresh as a 20 mM stock in100% DMSO and the DTNB is dissolved in 100% DMSO as a 100 mM stock andstored in the dark at room temperature. Both the substrate and DTNB arediluted together to 1 mM with substrate buffer (50 mM HEPES pH 7.5, 5 mMCaCl₂) before use. The stock of enzyme is diluted with assay buffer (50mM HEPES, pH 7.5, 5 mM CaCl₂, 0.02% Brij) to the desired finalconcentration. The assay buffer, enzyme, vehicle or inhibitor, andDTNB/substrate are added in this order to a 96 well plate (totalreaction volume of 200 μl) and the increase in color is monitoredspectrophotometrically for 5 minutes at 405 nm on a plate reader and theincrease in color over time is plotted as a linear line.

Alternatively, a fluorescent peptide substrate is used. In this assay,the peptide substrate contains a fluorescent group and a quenchinggroup. Upon cleavage of the substrate by an MMP, the fluorescence thatis generated is quantitated on the fluorescence plate reader. The assayis run in HCBC assay buffer (5 mM HEPES, pH 7.0, 5 mM Ca⁺², 0.02% Brij,0.5% Cysteine), with human recombinant MMP-1, MMP-9, or MMP-13. Thesubstrate is dissolved in methanol and stored frozen in 1 mM aliquots.For the assay, substrate and enzymes are diluted in HCBC buffer to thedesired concentrations. Compounds are added to the 96 well platecontaining enzyme and the reaction is started by the addition ofsubstrate. The reaction is read (excitation 340 nm, emission 444 nm) for10 min. and the increase in fluorescence over time is plotted as alinear line.

For either the thiopeptide or fluorescent peptide assays, the slope ofthe line is calculated and represents the reaction rate. The linearityof the reaction rate is confirmed (r² >0.85). The mean (x±sem) of thecontrol rate is calculated and compared for statistical significance(p<0.05) with drug-treated rates using Dunnett's multiple comparisontest. Dose-response relationships can be generated using multiple dosesof drug and IC₅₀ values with 95% CI are estimated using linearregression.

Procedure for Measuring TACE Inhibition

Using 96-well black microtiter plates, each well receives a solutioncomposed of 10 μL TACE (Immunex, final concentration 1 μg/mL), 70 μLTris buffer, pH 7.4 containing 10% glycerol (final concentration 10 mM),and 10 μL of test compound solution in DMSO (final concentration 1 μM,DMSO concentration<1%) and incubated for 10 minutes at room temperature.The reaction is initiated by addition of a fluorescent peptidylsubstrate (final concentration 100 μM) to each well and then shaking ona shaker for 5 sec.

The reaction is read (excitation 340 nm, emission 420 nm) for 10 min.and the increase in fluorescence over time is plotted as a linear line.The slope of the line is calculated and represents the reaction rate.

The linearity of the reaction rate is confirmed (r² >0.85). The mean(x±sem) of the control rate is calculated and compared for statisticalsignificance (p<0.05) with drug-treated rates using Dunnett's multiplecomparison test. Dose-response relationships can be generate usingmultiple doses of drug and IC₅₀ values with 95% CI are estimated usinglinear regression.

Results of the above in-vitro matrix metalloproteinase inhibition andTACE inhibition pharmacological assays are given in Table I below.

                  TABLE I    ______________________________________    Inhibition of MMP and TACE    Example   MMP-1.sup.1                        MMP-9.sup.1                                  MMP-13.sup.1                                          TACE.sup.1    ______________________________________    13        19.3(1)   57.3(10)    14        40(1)     66.8(10)    15        22.1(1)   930    16                  104.1    20        638.5     236.4     471.5    23        48.9(1)   38.4(300) 35(300)    26        1000      70        296     42%(1)    33        1227      15        47      294    ______________________________________     .sup.1. IC.sub.50 nM or % inhibition (concentration, μM)

Pharmaceutical Composition

Compounds of this invention may be administered neat or with apharmaceutical carrier to a patient in need thereof. The pharmaceuticalcarrier may be solid or liquid.

Applicable solid carriers can include one or more substances which mayalso act as flavoring agents, lubricants, solubilizers, suspendingagents, fillers, glidants, compression aids, binders ortablet-disintegrating agents or an encapsulating material. In powders,the carrier is a finely divided solid which is in admixture with thefinely divided active ingredient. In tablets, the active ingredient ismixed with a carrier having the necessary compression properties insuitable proportions and compacted in the shape and size desired. Thepowders and tablets preferably contain up to 99% of the activeingredient. Suitable solid carriers include, for example, calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Liquid carriers may be used in preparing solutions, suspensions,emulsions, syrups and elixirs. The active ingredient of this inventioncan be dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fat. The liquid carrier can containother suitable pharmaceutical additives such a solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, colors, viscosity regulators,stabilizers or osmo-regulators. Suitable examples of liquid carriers fororal and parenteral administration include water (particularlycontaining additives as above, e.g., cellulose derivatives, preferablesodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols, e.g., glycols) and their derivatives,and oils (e.g., fractionated coconut oil and arachis oil). Forparenteral administration the carrier can also be an oily ester such asethyl oleate and isopropyl myristate. Sterile liquid carriers are usedin sterile liquid form compositions for parenteral administration.

Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. Oral administration may be either liquid orsolid composition form.

The compounds of this invention may be administered rectally in the formof a conventional suppository. For administration by intranasal orintrabronchial inhalation or insufflation, the compounds of thisinvention may be formulated into an aqueous or partially aqueoussolution, which can then be utilized in the form of an aerosol. Thecompounds of this invention may also be administered transdermallythrough the use of a transdermal patch containing the active compoundand a carrier that is inert to the active compound, is non-toxic to theskin, and allows delivery of the agent for systemic absorption into theblood stream via the skin. The carrier may take any number of forms suchas creams and ointments, pastes, gels, and occlusive devices. The creamsand ointments may be viscous liquid or semi-solid emulsions of eitherthe oil in water or water in oil type. Pastes comprised of absorptivepowders dispersed in petroleum or hydrophilic petroleum containing theactive ingredient may also be suitable. A variety of occlusive devicesmay be used to release the active ingredient into the blood stream suchas a semipermeable membrane covering a reservoir containing the activeingredient with or without a carrier, or a matrix containing the activeingredient. Other occlusive devices are known in the literature.

The dosage to be used in the treatment of a specific patient suffering aMMP or TACE dependent condition must be subjectively determined by theattending physician. The variables involved include the severity of thedysfunction, and the size, age, and response pattern of the patient.Treatment will generally be initiated with small dosages less than theoptimum dose of the compound. Thereafter the dosage is increased untilthe optimum effect under the circumstances is reached. Precise dosagesfor oral, parenteral, nasal, or intrabronchial administration will bedetermined by the administering physician based on experience with theindividual subject treated and standard medical principles.

Preferably the pharmaceutical composition is in unit dosage form, e.g.,as tablets or capsules. In such form, the composition is sub-divided inunit dose containing appropriate quantities of the active ingredient;the unit dosage form can be packaged compositions, for example packedpowders, vials, ampoules, prefilled syringes or sachets containingliquids. The unit dosage form can be, for example, a capsule or tabletitself, or it can be the appropriate number of any such compositions inpackage form.

What is claimed:
 1. A compound having the formula: ##STR16## where thehydroxamic acid moiety and the sulfonamido moiety are bonded to adjacentcarbons of group A where:A is pyridyl; Z is aryl, where aryl is phenyl,naphthyl, or phenyl fused to a heteroaryl, a 5-6 membered heteroarylgroup having from 1 to 3 heteroatoms independently selected from N, O,and S, wherein this aryl and heteroaryl may be optionally substituted byR¹, R², R³ and R⁴ ; R¹, R², R³ and R⁴ are independently defined as --H,--COR⁵, --F, --Br, --Cl, --I, --C(O)NR⁵ OR⁶, --CN, --OR⁵, --C₁ -C₄-perfluoroalkyl, --S(O)_(x) R⁵ where x is 0-2, --OPO(OR⁵)OR⁶,--PO(OR⁶)R⁵, --OC(O)NR⁵ R⁶, --COOR⁵, --CONR⁵ R⁶, --SO₃ H, --NR⁵ R⁶,--NR⁵ COR⁶, --NR⁵ COOR⁶, --SO₂ NR⁵ R⁶, --NO₂, --N(R⁵)SO₂ R⁶, --NR⁵ CONR⁵R⁶, --NR⁵ C(═NR⁶)NR⁵ R⁶, 3-6 membered cycloheteroalkyl having one tothree heteroatoms independently selected from N, O, and S, optionallyhaving 1 or 2 double bonds and optionally substituted by one to threegroups each selected independently from R⁵, -aryl or heteroaryl asdefined above, SO₂ NHCOR⁵ or --CONHSO₂ R⁵ where R⁵ is not H,-tetrazol-5-yl, --SO₂ NHCN, --SO₂ NHCONR⁵ R⁶ or straight chain orbranched --C₁ -C₆ alkyl, --C₃ -C₆ -cycloalkyl optionally having 1 or 2double bonds, --C₂ -C₆ -alkenyl,or --C₂ -C₆ -alkynyl each optionallysubstituted with --COR⁵, --CN, --C₂ -C₆ alkenyl, --C₂ -C₆ alkynyl,--OR⁵, --C₁ -C₄ -perfluoroalkyl, --S(O)_(x) R⁵ where x is 0-2,--OC(O)NR⁵ R⁶, --COOR⁵, --CONR⁵ R⁶, --SO₃ H, --NR⁵ R⁶, --NR⁵ COR⁶, --NR⁵COOR⁶, --SO₂ NR⁵ R⁶, --NO₂, --N(R⁵)SO₂ R⁶, --NR⁵ CONR⁵ R⁶, --C₃ -C₆cycloalkyl as defined above, --C₃ -C₆ cycloheteroalkyl as defined above,-aryl or heteroaryl as defined above, --SO₂ NHCOR⁵ or --CONHSO₂ R⁵ whereR⁵ is not hydrogen, --OPO(OR⁵)OR⁶, --PO(OR⁶)R⁵, -tetrazol-5 -yl,--C(O)NR⁵ OR⁶, --NR⁵ C(═NR⁶)NR⁵ R⁶, --SO₂ NHCONR⁵ R⁶ or --SO₂ NHCN; withthe proviso that when R¹ and R² are on adjacent carbons of A, R¹ and R²together with the carbons to which they are attached can form a 5-7membered saturated or unsaturated carbocyclic ring or heterocyclic ringcontaining one to two heteroatoms selected independently from N, O, andS, each optionally substituted with one to four groups selectedindependently from R⁴ ; R⁵ and R⁶ are independently H, aryl andheteroaryl as defined above, --C₃ -C₆ -cycloalkyl as defined above, --C₃-C₆ -cycloheteroalkyl as defined above, --C₁ -C₄ -perfluoroalkyl, orstraight chain or branched --C₁ -C₆ alkyl, --C₂ -C₆ -alkenyl, or --C₂-C₆ -alkynyl each optionally substituted with --OH, --COR⁸, --CN,--C(O)NR⁸ OR⁹, --C₂ -C₆ -alkenyl, --C₂ -C₆ -alkynyl, --OR⁸, --C₁ -C₄-perfluoroalkyl, --S(O)_(x) R⁸ where x is 0-2, --OPO(OR⁸)OR⁹,--PO(OR⁸)R⁹, --OC(O)NR⁸ R⁹, --COOR⁸, --CONR⁸ R⁹, --SO₃ H, --NR⁸ R⁹,--NCOR⁸ R⁹, --NR⁸ COOR⁹, --SO₂ NR⁸ R⁹, --NO₂, --N(R⁸)SO₂ R⁹, --NR⁸ CONR⁸R⁹, --C₃ -C₆ cycloalkyl as defined above, --C₃ -C₆ -cycloheteroalkyl asdefined above, -aryl or heteroaryl as defined above, --SO₂ NHCOR⁸ or--CONHSO₂ R⁸ where R⁸ is not hydrogen, -tetrazol-5-yl, --NR⁸ C(═NR⁹)NR⁸R⁹, SO₂ NHCONR⁸ R⁹, --SO₂ NHCN; R⁷ is hydrogen, straight chain orbranched --C₁ -C₆ -alkyl, --C₂ -C₆ -alkenyl, or --C₂ -C₆ -alkynyl eachoptionally substituted with --OH, --COR⁵, --CN, --C₂ -C₆ -alkenyl, --C₂-C₆ -alkynyl, --OR⁵, --C₁ -C₄ -perfluoroalkyl, --S(O)_(x) R⁵ where x is0-2, --OPO(OR⁵)OR⁶, --PO(OR⁵)R⁶, --OC(O)NR⁵ R⁶, --COOR⁵, --CONR⁵ R⁶,--SO₃ H, --NR⁵ R⁶, --NR⁵ COR⁶, --NR⁵ COOR⁶, --SO₂ NR⁵ R⁶, --NO₂,--N(R⁵)SO₂ R⁶, --NR⁵ CONR⁵ R⁶, --C₃ -C₆ cycloalkyl as defined above,--C₃ -C₆ -cycloheteroalkyl as defined above, -aryl or heteroaryl asdefined above, --SO₂ NHCOR⁵ or --CONHSO₂ R⁵ where R⁵ is not hydrogen,-tetrazol-5-yl, --NR⁵ C(═NR6)NR⁵ R⁶, --C(O)N R⁵ OR⁶, --SO₂ NHCONR⁵ R⁶ or--SO₂ NHCN;or R⁷ is phenyl or naphthyl, optionally substituted by R¹,R², R³ and R⁴ or a 5 to 6 membered heteroaryl group having 1 to 3heteroatoms selected independently from N, O, and S and optionallysubstituted by R¹, R², R³ and R⁴ ; or R⁷ is C₃ -C₆ cycloalkyl or 3-6membered cycloheteroalkyl as defined above; R⁸ and R⁹ are independentlyH, aryl or heteroaryl as defined above, --C₃ -C₇ -cycloalkyl orcycloheteroalkyl as defined above, --C₁ -C₄ -perfluoroalkyl, straightchain or branched --C₁ -C₆ -alkyl, --C₂ -C₆ -alkenyl, or --C₂ -C₆-alkynyl, each optionally substituted with hydroxy, alkoxy, aryloxy,--C₁ -C₄ -perfluoroalkyl, amino, mono- and di-C₁ -C₆ -alkylamino,carboxylic acid, carboalkoxy and carboaryloxy, nitro, cyano, carboxamidoprimary, mono- and di-C₁ -C₆ -alkylcarbamoyl; a pharmaceuticallyacceptable salt thereof where one may be formed; and an optical isomeror diastereomer thereof where optical isomers and diastereomers exist.2. A compound according to claim 1 wherein both of the carbons of Aadjacent to the carbon bearing the sulfonamido group have a substituentother than hydrogen.
 3. A compound according to claim 2 wherein the Zgroup is para-alkoxyphenyl, para-aryloxyphenyl orpara-heteroaryloxyphenyl.
 4. A compound according to claim 3 which is3-Benzyl-(4-methoxy-benzenesulfonyl)-amino!-N-hydroxy-2,6-dimethoxy-isonicotinamide.5. A pharmaceutical composition comprising a pharmaceutical carrier anda therapeutically effective amount of a matrix metalloproteinase or TACEinhibiting compound according to claim
 1. 6. A method of inhibitingpathological changes mediated by matrix metalloproteinases in mammalswhich comprises administration to a mammal in need thereof atherapeutically effective amount of a matrix metalloproteinaseinhibiting compound according to claim
 1. 7. The method according toclaim 6 wherein the condition treated is atherosclerosis,atherosclerotic plaque formation, reduction of coronary thrombosis fromatherosclerotic plaque rupture, restenosis, MMP-mediated osteopenias,inflammatory diseases of the central nervous system, skin aging,angiogenesis, tumor metastasis, tumor growth, osteoarthritis, rheumatoidarthritis, septic arthritis, corneal ulceration, abnormal wound healing,bone disease, proteinuria, aneurysmal aortic disease, degenerativecartilage loss following traumatic joint injury, demyelating diseases ofthe nervous system, cirrhosis of the liver, glomerular disease of thekidney, premature rupture of fetal membranes, infammatory bowel disease,or periodontal disease.
 8. The method according to claim 6 wherein thecondition treated is age related macular degeneration, diabeticretinopathy, proliferative vitreoretinopathy, retinopathy ofprematurity, ocular inflammation, keratoconus, Sjogren's syndrome,myopia, ocular tumors, ocular angiogenesis/neovascularization andcorneal graft rejection.
 9. A method of inhibiting pathological changesmediated by TNF-α converting enzyme (TACE) in mammals which comprisesadministration to a mammal in need thereof a therapeutically effectiveamount of a TACE inhibiting compound according to claim
 1. 10. Themethod according to claim 9 wherein the condition treated is rheumatoidarthritis, graft rejection, cachexia, anorexia, inflammation, fever,insulin resistance, septic shock, congestive heart failure, inflammatorydisease of the central nervous system, inflammatory bowel disease, orHIV infection.